Association of the GNAS locus with severe malaria.
Functional studies have demonstrated an interaction between the stimulatory G protein alpha subunit (G-alpha-s) and the malaria parasite at a cellular level. Obstruction of signal transduction via the erythrocyte G-alpha-s subunit reduced invasion by Plasmodium falciparum parasites. We sought to determine whether this signal pathway had an impact at the disease level by testing polymorphisms in the gene encoding G-alpha-s (GNAS) for association with severe malaria in a large multi-centre study encompassing family and case-control studies from The Gambia, Kenya and Malawi, and a case-control study from Ghana. We gained power to detect association using meta-analysis across the seven studies, with an overall sample size approximating 4,000 cases and 4,000 controls. Out of 12 SNPs investigated in the 19 kb GNAS region, four presented signals of association (P < 0.05) with severe malaria. The strongest single-locus association demonstrated an odds ratio of 1.13 (1.05-1.21), P = 0.001. Three of the loci presenting significant associations were clustered at the 5-prime end of the GNAS gene. Accordingly, haplotypes constructed from these loci demonstrated significant associations with severe malaria [OR = 0.88 (0.81-0.96), P = 0.005 and OR = 1.12 (1.03-1.20), P = 0.005]. The evidence presented here indicates that the influence of G-alpha-s on erythrocyte invasion efficacy may, indeed, alter individual susceptibility to disease.
Auburn
Sarah
S
Wellcome Trust Centre for Human Genetics, Roosevelt Drive, Oxford, OX3 7BN, UK. sa3@sanger.ac.uk
Diakite
Mahamadou
M
Fry
Andrew E
AE
Ghansah
Anita
A
Campino
Susana
S
Richardson
Anna
A
Jallow
Muminatou
M
Sisay-Joof
Fatou
F
Pinder
Margaret
M
Griffiths
Michael J
MJ
Peshu
Norbert
N
Williams
Thomas N
TN
Marsh
Kevin
K
Molyneux
Malcolm E
ME
Taylor
Terrie E
TE
Koram
Kwadwo A
KA
Oduro
Abraham R
AR
Rogers
William O
WO
Rockett
Kirk A
KA
Haldar
Kasturi
K
Kwiatkowski
Dominic P
DP
D000349:Africa; D000483:Alleles; D000818:Animals; D016022:Case-Control Studies; D002648:Child; D002675:Child, Preschool; D002864:Chromogranins; D004912:Erythrocytes / Q000378:metabolism / Q000469:parasitology; D019205:GTP-Binding Protein alpha Subunits, Gs / Q000097:blood / Q000235:genetics*; D005787:Gene Frequency; D006239:Haplotypes; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D015810:Linkage Disequilibrium; D008288:Malaria / Q000097:blood / Q000235:genetics* / Q000469:parasitology; D020641:Polymorphism, Single Nucleotide; D015398:Signal Transduction
D002864:Chromogranins; C406732:GNAS protein, human; D019205:GTP-Binding Protein alpha Subunits, Gs